@article{6d9588e06d824d4ba0908e3ff62263da,
title = "Amikacin Liposome Inhalation Suspension for Refractory Mycobacterium avium Complex Lung Disease: Sustainability and Durability of Culture Conversion and Safety of Long-term Exposure",
abstract = "Background: In the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001). Research Question: In patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion? Study Design and Methods: Adults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation. Results: More patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment. Interpretation: In a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion. Trial Registry: ClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov",
keywords = "ALIS, Mycobacterium avium complex, culture conversion, durability, nontuberculous mycobacteria",
author = "{CONVERT Study Group} and Griffith, {David E.} and Rachel Thomson and Flume, {Patrick A.} and Aksamit, {Timothy R.} and Field, {Stephen K.} and Addrizzo-Harris, {Doreen J.} and Kozo Morimoto and Wouter Hoefsloot and Mange, {Kevin C.} and Yuen, {Dayton W.} and Monika Ciesielska and Wallace, {Richard J.} and {van Ingen}, Jakko and Brown-Elliott, {Barbara A.} and Chris Coulter and Winthrop, {Kevin L.}",
note = "Funding Information: Author contributions: D. E. G. was the principal investigator, designed the study, interpreted data, drafted the manuscript, and takes responsibility for the content of the manuscript, including the data and analysis. R. T. and P. A. F. were trial investigators and drafted the manuscript. K. C. M. and M. C. conducted the analysis and interpreted data. D. W. Y. designed the study, conducted the analysis, and interpreted data. T. R. A. S. K. F. D. J. A.-H. K. M. and W. H. were trial investigators. J. v. I. conducted microbiologic analyses and drafted the manuscript. R. J. W. B. A. B.-E. and C. C. conducted microbiologic analyses. K. L. W. was a coprincipal investigator and designed the study, interpreted data, and drafted the manuscript. All authors critically reviewed and approved the final manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST the following: D. E. G. reports grants, consultant fees, and personal fees from Insmed Incorporated during the conduct of the study and outside the submitted work. R. T. reports personal fees from Insmed Incorporated outside the submitted work. P. A. F. reports grants and personal fees from Insmed Incorporated during the conduct of the study. T. R. A. reports remuneration directed to the Mayo Foundation during the conduct of the study. S. K. F. reports grants from Insmed Incorporated during the conduct of the study and, outside the submitted work, grants from Canadian Institute of Health research, personal fees from Canadian Agency for Drugs and Technologies of Health, grants and personal fees from GSK, grants from Novartis, grants from Boehringer-Ingelheim, grants from AstraZeneca, personal fees from GSK, personal fees from Novartis, personal fees from Teva, and personal fees from Boehringer-Ingelheim. K. M. reports consultant fees from Insmed Incorporated outside the submitted work. K. C. M. is an employee of Insmed Incorporated. D. W. Y. is an employee of Insmed Incorporated. M. C. is an employee of Insmed Incorporated. R. J. W. reports grants from Insmed Incorporated. J. v. I. reports advisory board membership with Insmed Incorporated during the conduct of the study and, outside the submitted work, advisory board membership with Janssen Pharmaceuticals and Spero Therapeutics. B. A. B.-E. reports grants from Insmed Incorporated during the conduct of the study and grants from Insmed Incorporated outside the submitted work. C. C. reports financial support from Insmed Incorporated to perform laboratory-related trial work (consumables, technical staff costs) for Insmed Incorporated. K. L. W. reports grants and personal fees from Insmed Incorporated and personal fees from Johnson & Johnson, Paratek, RedHill Biopharma, Horizon, and Spero. None declared (D. J. A.-H. W. H.). Other contributions: Services for MAC culture, species identification, and susceptibility testing were provided by The University of Texas Health Science Center, Tyler, TX; Radboud University Medical Center, Nijmegen, The Netherlands; and the Queensland Mycobacterium Reference Laboratory, Herston, QLD, Australia. Services for MAC variable number tandem repeat typing were provided by The University of Texas Health Science Center, Tyler, TX. The following individuals served as national coordinators for CONVERT study sites in their respective countries: Bernd Lamprecht, MD (Austria); Dirk Wagner, MD, PhD (Germany); Charles Haworth, MD (United Kingdom); Wouter Hoefsloot, MD, PhD (The Netherlands); Luigi Codecasa, MD (Italy); Claire Andr{\'e}jak, MD (France); Jordi Dorca-Sargatal, MD (Spain); Janusz Milanowski, MD, PhD (Poland); and Ronny {\"O}hman, MD, PhD (Sweden). The authors thank the patients and their families for their support and participation and the study investigators, study coordinators, and support staff across all sites; former Insmed Incorporated employees Gina Eagle, MD, who oversaw the design and conduct of the CONVERT study, and James Nezamis, MS, who led the development of the statistical analysis plan and the analysis of the results of CONVERT. Writing assistance was provided by Kristen A. Andersen, PhD, of MediTech Media, Ltd. (Hamilton, NJ), funded by Insmed Incorporated. Additional information: The e-Appendixes and e-Tables can be found in the Supplemental Materials section of the online article. FUNDING/SUPPORT: This work was funded by Insmed Incorporated, Bridgewater, NJ. Funding Information: FUNDING/SUPPORT: This work was funded by Insmed Incorporated, Bridgewater, NJ. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = sep,
doi = "10.1016/j.chest.2021.03.070",
language = "English (US)",
volume = "160",
pages = "831--842",
journal = "Diseases of the chest",
issn = "0012-3692",
publisher = "American College of Chest Physicians",
number = "3",
}